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Enhanced Degradation of I-B Contributes to Endogenous Activation of NF-B in Hs294T Melanoma Cells¹

Departments of Cell Biology and Medicine, Division of Dermatology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2175, and Veterans Affairs Medical Center, Nashville, Tennessee 37212-2637

The expression of the CXC chemokine MGSA is often deregulated during viral infection, chronic inflammation, and melanoma tumor progression. In Hs294T melanoma cells, the increased constitutive expression of MGSA is due to increased gene transcription. Moreover, nuclear extracts from unstimulated Hs294T cells contain 19-fold more immunoreactive NF-B p65 than that observed in normal retinal pigment epithelial (ARPE) cells. This increase in NF-B p65 correlates with increased NF-B DNA binding activity in Hs294T nuclear extracts. After stimulation with interleukin 1, Western and electrophoretic mobility shift assay analysis indicate that in both cell types, additional activated NF-B p65 is translocated to the nucleus. However, the rate of postinduction repression of NF-B DNA binding is delayed in Hs294T melanoma cells compared to ARPE cells. Western analysis of whole-cell lysates from both Hs294T and ARPE cells indicates that protein levels of the inhibitor of NF-B, I-B, are 3-fold lower in Hs294T cells. The decrease in I-B cannot be attributed to alterations in the transcription or translation of I-B. Rather, the posttranslational processing has been altered. In Hs294T cells, the half-life of the I-B protein is 45 min, compared to 120 min in ARPE cells. These results indicate that in Hs294T melanoma cells the equilibrium between I-B degradation and resynthesis has been altered, leading to constitutive nuclear translocation and activation of NF-B. Similar mechanisms could also operate in other tumorigenic processes, as well as in viral and chronic inflammatory disorders, to produce high constitutive and unregulated chemokine expression.

¹ This work was supported by NCI Grant CA56704, the Department of Veterans Affairs Merit and Associate Career Scientist Award, and NIH Grant 5P30 AR41943.

² To whom requests for reprints should be addressed, at Department of Cell Biology, Vanderbilt University School of Medicine, 1161 21st Avenue South. Nashville, TN 37232-2175. Phone: (615) 343-7777; Fax: (615) 343-4539; E-mail: ann.richmond@mcmail.vanderbilt.edu.

Received 1/ 6/97. Accepted 5/15/97.

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